tbuckley/cabot-search huggingface dataset:
Implementation Strategies Used and Reported in Brief Suicide Prevention Intervention Studies
Authors: Brittany N. Rudd, Molly Davis, Stephanie Doupnik, Catalina Ordorica, Steven C. Marcus, Rinad S. Beidas
Journal: JAMA Psychiatry (2022)

This survey study investigates the implementation strategies researchers used to support brief suicide prevention interventions in their efficacy and effectiveness studies and compares the results with implementation strategies reported in their study publications.
Abstract 1792: FGFR3 mediated PARP1 tyrosine 158 phosphorylation promotes PARP inhibitor resistance
Authors: MeiKuang Chen, Yuan Gao, Weiya Xia, Yu-Han Wang, Jennifer K. Litton, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Yongkun Wei, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T. Albarracin, Shao-Chun Wang, Ying-Nai Wang, Gabriel N. Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung
Journal: Cancer Research (2022)

Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which induce DNA damage by inhibiting PARP1 enzymatic activity and trapping PARP on the damaged DNA, are used to eliminate BRCA1/2-mutated (BRCAm) cancer. However, clinical observations suggest that BRCAm tumors develop PARPi resistance. Current strategies to overcome PARPi resistance include impeding multiple DNA repair pathways to induce excessive DNA damage. Here, we propose a novel strategy targeting oncogenic receptor tyrosine kinases to enhance PARP trapping. By developing triple-negative breast cancer (TNBC) cells with acquired talazoparib resistance, we observed a high prevalence of activated fibroblast growth factor receptor 3 (FGFR3) kinase in these cells through kinase antibody array analysis. Mass spectrometry analysis and in vitro kinase assay suggested that FGFR3 phosphorylated PARP1 at tyrosine residues 158 and 176. Biochemistry studies suggested that only PARP1 tyrosine 158 phosphorylation contributes to PARPi resistance in the cells we developed. We then developed a monoclonal antibody against tyrosine 158 phosphorylated PARP1, and found that high-level PARP1 tyrosine 158 phosphorylation positively correlated with PARPi resistance in breast cancer patient-derived xenograft models. We further demonstrated that the combination of FGFR inhibitor and PARPi delayed DNA repair with prolonged PARP trapping. Moreover, synergy between PARPi and FGFR inhibition was observed in multiple TNBC cell lines with PARPi resistance in vitro. The combination of PARPi and FGFR inhibitor also showed synergism in vivo, and treatment with the combination of PARPi and FGFR inhibitor was tolerated in mouse models. These findings reveal that PARP1 tyrosine 158 phosphorylation facilitates resolving of the PARPi-induced PARP-trapping, and that the tyrosine 158 phosphorylated PARP1 may be an effective biomarker to indicate FGFR3 mediated PARPi resistance. Citation Format: MeiKuang Chen, Yuan Gao, Weiya Xia, Yu-Han Wang, Jennifer K. Litton, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Yongkun Wei, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T. Albarracin, Shao-Chun Wang, Ying-Nai Wang, Gabriel N. Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung. FGFR3 mediated PARP1 tyrosine 158 phosphorylation promotes PARP inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1792.
Tree House Explorer: A Novel Genome Browser for Phylogenomics
Authors: Andrew J Harris, Nicole M Foley, Tiffani L Williams, William J Murphy
Journal: Molecular Biology and Evolution (2022)

Abstract Tree House Explorer (THEx) is a genome browser that integrates phylogenomic data and genomic annotations into a single interactive platform for combined analysis. THEx allows users to visualize genome-wide variation in evolutionary histories and genetic divergence on a chromosome-by-chromosome basis, with continuous sliding window comparisons to gene annotations, recombination rates, and other user-specified, highly customizable feature annotations. THEx provides a new platform for interactive phylogenomic data visualization to analyze and interpret the diverse evolutionary histories woven throughout genomes. Hosted on Conda, THEx integrates seamlessly into new or pre-existing workflows.
Abstract 289: A novel <i>ex-vivo</i> organotypic culture platform for functional interrogation of human appendiceal neoplasms
Authors: Jonathan Weitz, Tatiana Hurtado de Mendoza, Herve Tiriac, Joel Baumgartner, Kaitlyn Kelly, Jula Veerapong, Andrew Lowy
Journal: Cancer Research (2022)

Abstract Appendiceal neoplasms are rare and often clinically present with peritoneal metastasis. While surgical tumor resection is effective for some types of primary appendiceal cancers, patients with metastatic disease have poor prognostic outcomes. Models to study appendix cancer biology are limited, given that 1) no mouse models exist and 2) reliable in vitro models are unavailable. As such, we have developed an ex-vivo organotypic slice model to examine cellular interactions between tumor cells and their local microenvironment. Tumor specimens from human appendiceal cancer patients were cut using a vibratome to make 200 μm organotypic slices. Slices were cultured on transwell inserts and tested for changes in morphological, cellular and functional characteristics over a seven-day period. Organotypic slices maintained their cellular composition in regard to the proportion of epithelial, immune cells and fibroblasts. Live cell [Ca2+]i imaging of long term cultured slices confirmed that immune cells remain functionally active when stimulated with extracellular ATP. Lasty, using tumor biopsies from human donors, we have identified a diverse immunological profile of appendiceal tumors not previously identified. Our study illustrates a novel approach for studying the pathophysiology of appendiceal cancer, a notoriously difficult disease to model. Citation Format: Jonathan Weitz, Tatiana Hurtado de Mendoza, Herve Tiriac, Joel Baumgartner, Kaitlyn Kelly, Jula Veerapong, Andrew Lowy. A novel ex-vivo organotypic culture platform for functional interrogation of human appendiceal neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 289.
Abstract 1159: Predicting clinical drug responses using a few-shot learning-based interpretable AI
Authors: Sungjoon Park, Akshat Singhal, Erica Silva, Jason F. Kreisberg, Trey Ideker
Journal: Cancer Research (2022)

Abstract High-throughput screens have generated large amounts of data characterizing how thousands of cell lines respond to hundreds of anti-cancer therapies. However, predictive drug response models trained using data from cell lines often fail to translate to clinical applications. Here, we focus on two key issues to improve clinical performance: 1) Transferability: the ability of predictive models to quickly adapt to clinical contexts even with a limited number of samples from patients, and 2) Interpretability: the ability to explain how drug-response predictions are being made given an individual patient’s genotype. Notably, an interpretable AI model can also help to identify biomarkers of treatment response in individual patients. By leveraging new developments in meta-learning and interpretable AI, we have developed an interpretable drug response prediction model that is trained on large amounts of data from experiments using cell lines and then transferred to clinical applications. We assessed our model’s clinical utility using AACR Project GENIE data, which contains mutational profiles from tumors and the patient’s therapeutic responses. We have demonstrated the feasibility of applying our AI-driven predictive model to clinical settings and shown how this model can support clinical decision making for tumor boards. Citation Format: Sungjoon Park, Akshat Singhal, Erica Silva, Jason F. Kreisberg, Trey Ideker. Predicting clinical drug responses using a few-shot learning-based interpretable AI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1159.
Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration
Authors: Emily F Higgs, Riyue Bao, Ken Hatogai, Thomas F Gajewski
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background A T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration in tumors is critical for expanding immunotherapy efficacy. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade. Methods RNA sequencing and clinical data were obtained for Wilms tumor, rhabdoid tumor, osteosarcoma, and neuroblastoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and adult cancers from The Cancer Genome Atlas (TCGA). Using an 18-gene tumor inflammation signature (TIS) representing activated CD8 + T cells, we identified genes inversely correlated with the signature. Based on these results, adult tumors were also analyzed, and immunofluorescence was performed on metastatic melanoma samples to assess the MSH2 relationship to anti-programmed cell death protein-1 (PD-1) efficacy. Results Among the four pediatric cancers, we observed the lowest TIS scores in Wilms tumor. TIS scores were lower in Wilms tumors compared with matched normal kidney tissues, arguing for loss of endogenous T cell infiltration. Pathway analysis of genes upregulated in Wilms tumor and anti-correlated with TIS revealed activated pathways involved DNA repair. The majority of adult tumors in TCGA also showed high DNA repair scores associated with low TIS. Melanoma samples from an independent cohort revealed an inverse correlation between MSH2 + tumor cells and CD8 + T cells. Additionally, melanomas with high MSH2 + tumor cell numbers were largely non-responders to anti-PD-1 therapy. Conclusions Increased tumor expression of DNA repair genes is associated with a less robust immune response in Wilms tumor and the majority of TCGA tumor types. Surprisingly, the negative relationship between DNA repair score and TIS remained strong across TCGA when correcting for mutation count, indicating a potential role for DNA repair genes outside of preventing the accumulation of mutations. While loss of DNA repair machinery has been associated with carcinogenesis and mutational antigen generation, our results suggest that hyperexpression of DNA repair genes might be prohibitive for antitumor immunity, arguing for pharmacologic targeting of DNA repair as a potential therapeutic strategy.
Abstract 5067: Identify the combination efficacy and immune regulation of Abraxane combines with human IL-15 albumin binding domain fusion protein on pancreatic ductal adenocarcinoma animal model
Authors: Po-Fu Yueh, Fei-Ting Hsu, Keng-Li Lan
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the hardest medical challenge in the world. Nab-paclitaxel is significantly more effective chemotherapy drugs than paclitaxel formulated as Cremophor EL. In this study, we reported the immune effect of Abraxane to combine with our new design recombinant human IL-15 fused with albumin binding domain (hIL-15-ABD) on subcutaneously Panc02 and orthotopically KPC PDAC animal models. In our results, the combination treatment greatly reduced the subcutaneous tumor growth in Panc02 and KPC bearing models, compared with vehicle group. Furthermore, the combinational therapy successfully buildup the anticancer immunity microenvironment (TME) through increasing the activation of effector cells, such as of NK cells (CD3-/CD49b+/NK1.1+) and CD8+ T (CD8+/IFN-γ+/IL-2+) cells. Moreover, combination therapy may also decrease the accumulation of immunosuppressvie cells such as MDSCs (CD11b+/Gr-1+) and Tregs (CD4+/CD25+/Foxp3+). The combination of Abraxane and hIL-15-ABD were also reduced the NF-κB-mediated immunosuppressive markers, including IDO, Foxp3 and VEGF. In conclusion, Abraxane combined with hIL-15-ABD enhanced immue effector cells involved in both innate and adaptive immunities, reduced the TME’s immunosuppressive cells, and displayed superior inhibitory effect on both subcutaneous and orthotopic syngeneic murine pancreatic ductal adenocarcinoma models than that of either monotherapy. These results suggest that combinational therapy of Abraxane and hIL-15-ABD could be a promising treatment stratedgy for PDAC. Citation Format: Po-Fu Yueh, Fei-Ting Hsu, Keng-Li Lan. Identify the combination efficacy and immune regulation of Abraxane combines with human IL-15 albumin binding domain fusion protein on pancreatic ductal adenocarcinoma animal model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5067.
Abstract 5230: Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable esophageal squamous carcinoma: an open-label, single-arm study
Authors: Bo Jiang, Xin Yang, Junling Zhang, Mengli Huang
Journal: Cancer Research (2022)

Abstract Objective: Although neoadjuvant chemotherapy has been recommended for resectable ESCC patients, the 5-year overall survival rate was less than 50%. Immune checkpoint inhibitors have been shown to be efficient for advanced ESCC, while few studies focus on the neoadjuvant immunotherapy combined with chemotherapy. Herein, we designed a trial to evaluate the safety and efficacy of neoadjuvant PD-1 inhibitors in combination with chemotherapy for resectable ESCC. Methods: All patients had treatment-naïve resectable ESCC (stage III) that were confirmed by histopathology. All patients were scheduled to receive surgery within 4-6 weeks after neoadjuvant treatment (2 cycles) consisting of PD-1 inhibitors (Camrelizumab 200mg or Sintilimab 200 mg or Tislelizumab 200 mg) combined with two conventional chemotherapy regimens (Cisplatin + paclitaxel). The primary endpoint was the major pathologic response (MPR). Secondary endpoints were disease-free survival (DFS), R0 resection rate and safety profile. Immune signature of immune cells were evaluated in surgical specimens using immunofluorescence. Results: Between Aug. 1, 2020, and Oct. 1, 2021, we assessed 10 patients for screening, of whom 10 patients were enrolled. Neoadjuvant therapy was not associated with delays in surgery or increased surgical complications/mortality. The median follow-up was 5.0 months (range 2.0∼31.0 months). Ten (100.0%) successfully underwent R0 resection. Of the 10 evaluable patients, 6 (60.0%) were MPR, 4 (40.0%) were pathologic complete response (pCR). Imaging evaluation was feasible in all patients. Partial response (PR) was achieved in 1 (10.0%) and stable disease (SD) was observed in 8 (80.0%). The most common treatment-related grade 1-2 adverse events were anemia (5, 50.0%), nausea (3, 30.0%), vomiting (3, 30.0%), constipation (2, 20.0%) and myelosuppression (2, 20.0%). There was no grade 3-4 events and treatment-related deaths. The presence of CD3+ T cells, B cell, and CD56 bright were statistically comparable patient groups of MPR and pCR, with an increased tendency in pCR patients. In addition, macrophages, CD8+ T cells, PD-1+CD8+ T cell, Treg cells, and PD-L1+CD68+ cells in pCR patients showed a downward trend. Conclusions: Neoadjuvant PD-1 inhibitors plus chemotherapies had manageable treatment-related toxic effects. This regimen induced pCR or MPR in 100.0% of resected tumor, demonstrating its antitumor efficacy in resectable ESCC. Citation Format: Bo Jiang, Xin Yang, Junling Zhang, Mengli Huang. Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable esophageal squamous carcinoma: an open-label, single-arm study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5230.
Tracking the 2022 monkeypox outbreak with epidemiological data in real-time
Authors: Moritz U G Kraemer, Houriiyah Tegally, David M Pigott, Abhishek Dasgupta, James Sheldon, Eduan Wilkinson, Marinanicole Schultheiss, Aimee Han, Mark Oglia, Spencer Marks, Joshua Kanner, Katelynn O'Brien, Sudheer Dandamudi, Benjamin Rader, Kara Sewalk, Ana I Bento, Samuel V Scarpino, Tulio de Oliveira, Isaac I Bogoch, Rebecca Katz, John S Brownstein
Journal: The Lancet Infectious Diseases (2022)
Abstract 2948: A multimodal, label-free tool for gentle and efficient cell separation
Authors: Kevin Travers, Chris Stevens, Susana Jett, Suzanne Weaver, Teddy de Groot, Stefan Ha, Geoff Facer, Kathy Lazaruk
Journal: Cancer Research (2022)

Abstract LevitasBio has developed the LeviCell™ platform, a powerful new technology for cell separation and characterization that utilizes magnetic fields to levitate cells. Unlike other methods, cell separation via magnetic levitation does not require dyes, antibodies or specific markers, and the cells are not modified or perturbed in any fashion. However, magnetic levitation also does not preclude the use of these tools to further enhance separation of cells. In its simplest form, magnetic levitation requires only the addition of an inert paramagnetic compound to the media in which the cells are suspended. The cells are subsequently introduced into an externally applied magnetic field while contained within a single-use cartridge, which causes the cells to levitate in solution. The cells’ intrinsic properties, including density and magnetic susceptibility, determine the height to which the cells levitate. As different cell types often have different such properties, they may often levitate to different heights, facilitating their separation. Continuous imaging allows for complete sample analysis and characterization with the benefit of real-time control over the cell separation. The simplicity of magnetic levitation enables cells to be treated gently without use of high pressure or other perturbations that commonly lead to increased cellular stress responses, specific cell type activation, or even cell death. The direct and gentle flow path leads to high yields of live cells even with very low input cell numbers. This novel cell separation technology enables a variety of applications, including: the enrichment of viable cells from dead/dying cells and debris; separation of different cell types possessing distinct densities; and, in cases where the intrinsic density changes, the separation of differentiated from undifferentiated cells. Given that the levitation chamber is flanked by two magnets on the top and bottom, the levitation technology also inherently allows for the use of magnetic particles to deplete undesired cells within a cell population. Here we illustrate the performance of anti-CD45 antibody-conjugated magnetic particles for CD45+ cell depletion with the LeviCell system. CD45+ depletion rates of greater than 99% are readily obtained across a wide range of total CD45+ input cell numbers, from 105 to 107 total cells. Furthermore, CD45+ cell depletion is performed simultaneously with live cell enrichment, allowing for the collection of a high viability CD45- live cell population. Citation Format: Kevin Travers, Chris Stevens, Susana Jett, Suzanne Weaver, Teddy de Groot, Stefan Ha, Geoff Facer, Kathy Lazaruk. A multimodal, label-free tool for gentle and efficient cell separation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2948.
Abstract 3170: Human retroviral sequences transcription in glioma/glioblastoma sample
Authors: Adam J. Lassak, Monika Rak, Melody C. Baddoo, Hui-Yi Lin, Krzysztof Reiss
Journal: Cancer Research (2022)

Abstract In glioblastoma patients, expansion of glioma initiating cells (GICs), a discrete population of cells demonstrating stem-like phenotype, is often associated with drug resistance development and ultimately cancer recurrence. Therefore a better understanding of the molecular and cellular mechanisms underlying the origin of GICs is critical to develop new therapies better targeting glioblastoma. Human endogenous retroviral sequences (HERVs), present in approximately 500,000 copies and comprising nearly 8% of the human genome, may serve as an abundant genetic material equipping GIC with phenotypic plasticity needed to develop stem-like phenotype. Recent epigenomic and transcriptomic data show HERV activation during early human development. Moreover, increased HERV transcription is observed in OCT4/SOX2/KLF4/c-MYC induced pluripotent cells. Finally, activation of HERV loci transcription is also commonly observed in different tumor types. Using publicly available The Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) RNA-seq data collection, we have quantified transcripts for all 13,208 HERV loci annotated in the RepBase database. To improve the accuracy of quantifying the HERV transcriptomic landscape, we reassigned already mapped fragments to the most probable transcript using the Telescope software. Our comprehensive approach allowed us to identify the set of HERV loci uniquely dysregulated in the glioblastoma compared to normal brain tissue. In addition, we compared 540 low-grade glial tumors from TCGA-LGG project (classified as grade II and III gliomas) with 165 glioblastoma samples from TCGA-GBM (classified as grade IV gliomas) using the same bioinformatics pipeline. Comprehensive analysis of transcript levels allowed us to identify HERV assemblage differentially expressed between these two patient cohorts. The correlation between HERV and ORF transcript levels show strong coregulation of HERVs expression with genes involved in establishing/maintaining embryonic/neural/glial stem cells phenotype. To confirm our observations we have up- or downregulated HERV loci combining guide RNA array targeting robustly approximately 90% of HERV LTR5Hs elements with a vector expressing CRISPR-based transcriptional activator or repressor. Downregulation of HERV transcription with this system was associated with the inhibition of clonogenic growth in cell culture. In summary, this study sets the stage for identifying HERV loci that could serve as potential GIC biomarkers, as well as the molecular targets for GIC elimination. Citation Format: Adam J. Lassak, Monika Rak, Melody C. Baddoo, Hui-Yi Lin, Krzysztof Reiss. Human retroviral sequences transcription in glioma/glioblastoma sample [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3170.